Glaucomas are a family of ocular disorders usually characterized by an increased intraocular pressure (IOP) with a typical damage to the optic nerve and the visual field; but many exceptions exist. The level of IOP is the net result of production minus outflow from the eye, via a ring-like sieve structure called the trabecular meshwork, located at the angle of the anterior chamber. While most of the hypertensive glaucomas result from increased trabecular resistance to outflow, most of the medical therapy focuses on decreasing the inflow (See Shields M. B.: Textbook of Glaucoma, 4th Ed., Williams & Wilkins, Baltimore, 1998). Every minute approximately 1.8-4.2 microliter of aqueous humor is produced and secreted into the posterior chamber of the eye by the non-pigmented ciliary epithelium. The process is not well understood, but seems to involve a combination of active ultrafiltration and passive transport. The rate of secretion is influenced by multiple factors, e.g. diurnal curve, pH, age, enzymes like carbonic anhydrase (CA) as well as vascular diseases. Several anti-glaucoma drug classes influence various stages of the aqueous humor flow, e.g. beta-adrenoreceptor antagonists (timolol, betaxolol) systemic and topical carbonic anhydrase (CA) inhibitors (acetazolamide, dorzolamide, See Sharir M.: Novel Thiadiazole Sulfonamide Carbonic Anhydrase Inhibitors as Topically Effective Ocular Hypotensive Agents, PhD Thesis, University of Louisville, Louisville, Ky., USA, May 1990), alpha adrenoreceptor agonists (brimonidine, apraclonidine) and prostaglandin analogues (latanoprost, bimatoprost) to name a few. Most drug groups act synergistically to decrease aqueous humor production and secretion by up to 50% with some ‘unconventional’ outflow additive effect of the prostaglandins. Studies in aqueous humor dynamics elicited some pivotal components in the secretion processes. While bicarbonate is found in higher than plasma concentration in the posterior chamber of the rabbit (probably a direct result of CA involvement), it is not the case in humans, where chloride has been suggested as the key anion.
The mechanism of fluid secretion across semi-permeable/selective tissue membranes in the human body shares similarities in most organ systems. At some point, in the cell membrane, “water splitting” occurs: the proton follows an anion (to maintain electro-neutrality) and gets to one side while the hydroxyl usually couples with sodium or another positively charged component and ends up in the contra-lateral side of the cell membrane. The substrate used for this water splitting is carbon dioxide, which gets hydrated to form the (weak) carbonic acid; consequently its proton and bicarbonate are separated by the cell membrane. This process generates passive water secretion, to accompany the electrolytes and maintain both electric and osmotic equilibrium. The reaction is catalyzed by CA.
Aqueous humor is produced and secreted into the posterior chamber of the eye by the non-pigmented ciliary epithelium, similarly to the cerebrospinal fluid (CSF), formed by the choroidal plexus and secreted across the floor of the brain ventricles. A basolateral Chloride/Bicarbonate-anion exchanger switches between the two and it is suggested that succinimides, by way of disrupting first the T-calcium channels and then the anion equilibrium, disrupt aqueous humor production, hence decreasing the intraocular pressure.
The typical absence epilepsy of childhood is a non-convulsive form of epilepsy that is characterized by frequent “absences” and bilaterally synchronous 3/s spike and wave electroencephalographic features, often called ‘spike-wave-discharge’(SWD). Absence seizures are idiopathic and are divided according to the age of onset to childhood absence epilepsy (CAE, or pyknolepsy), juvenile absence epilepsy (JAE) and juvenile myoclonic epilepsy (JME or impulsive Petit Mal seizures). All these conditions are associated with the SWD pattern, and seizures that may last from few seconds to minutes, sometimes several hundred attacks per day. The pathogenesis is still unknown. Multiple studies suggest that epilepsy can result from processes which disturb extracellular ion homeostasis, alter energy metabolism, change receptor function or alter transmitter uptake. Recent studies suggest that a reverberant, thalamo-cortical neuronal circuitry underlies the SWD seizures. (See Huguenard J. R.: Neuronal Circuitry of Thalamocortical Epilepsy and Mechanism of Anti-absence Drug Action. In: Jasper's Basic Mechanism of the Epilepsies, 3rd Ed., Advances in Neurology, Vol. 79, Chapter 67, edited by A. V. Delgado-Escueta et. al. Lippincott Williams & Wilkins, Philadelphia, 1999). Ethosuximide and its methsuximide metabolite may exert their action through alteration in thalamic cellular excitability, possibly by blocking the T-type calcium current, while a tetramethyl derivative might cause convulsions (Coulter D. A., Huguenard J. R., Prince D. A.: Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann. Neurol. 1989; 25:582-593.). While T-channel blockade is important, it is not the sole anti-absence drug mechanism. The effectiveness of the benzodiazepine clonazepam in ameliorating absence epilepsy suggested that the GABA receptor system is important as well as a wider network of neuronal system. Other theories suggest that some of the CAE or JAE, especially the hereditary types are because of defects in CLCN-2 (Chloride channel Protein 2).
U.S. Pat. No. 4,981,867 discloses the use of succinimides, including the anti-convulstant and anti-epileptic drugs ethosuximide, methsuximide and phensuximide, for treating for reducing tremor.
U.S. Pat. No. 4,188,398 teaches antiepileptic activity of □-/para-isopropyloxyphenyl/succinimides.
U.S. Pat. No. 4,609,663 teaches a method of treating glaucoma by administering aldose reductase inhibitors including spiro fluoren-, or indeno[1,2]b]pyridine-succinimide derivatives.
U.S. Pat. Publication No. 2005/0175690 discloses oral drug compositions comprising a pharmaceutical agent and a solubilizing agent, wherein the pharmaceutical agent is selected from a low solubility pharmaceutical agent or a low dissolution rate pharmaceutical agent. The low solubility pharmaceutical agent is preferably other than ethosuximide, methsuximide, and phensuximide. U.S. 2005/0175690 does not teach ophthalmic pharmaceutical formulations.
There is an unmet need for new therapies for treating ocular disorders associated with elevated intraocular pressure, such as glaucomas.